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Effects of C-17 heterocyclic substituents on the anticancer activity of 2-ethylestra-1,3,5(10)-triene-3-O-sulfamates : synthesis, in vitro evaluation and computational modelling


Reference:

Jourdan, F., Bubert, C., Leese, M. P., Smith, A., Ferrandis, E., Regis-Lydi, S., Newman, S. P., Purohit, A., Reed, M. J. and Potter, B. V. L., 2008. Effects of C-17 heterocyclic substituents on the anticancer activity of 2-ethylestra-1,3,5(10)-triene-3-O-sulfamates : synthesis, in vitro evaluation and computational modelling. Organic and Biomolecular Chemistry, 6 (22), pp. 4108-4119.

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Official URL:

http://dx.doi.org/10.1039/b810300c

Abstract

The potent activity of 2-substituted estra-1,3,5(10)-triene-3-O-sulfamates against the proliferation of cancer cells in vitro and tumours in vivo highlights the therapeutic potential of such compounds. Optimal activity is derived from a combination of a 2-XMe group ( where X = CH2, O or S), a 3-O-sulfamate group in the steroidal A-ring and a H-bond acceptor around C-17 of the D-ring. Herein, we describe the synthesis and anti-proliferative activities of a series of novel 2-substituted estra-1,3,5( 10)-triene-3-O-sulfamates bearing heterocyclic substituents ( oxazole, tetrazole, triazole) tethered to C-17. In vitro evaluation of these molecules revealed that high anti-proliferative activity in breast and prostate cancer cells lines (GI(50) of 340-850 nM) could be retained when the heterocyclic substituent possesses H-bond acceptor properties. A good correlation between the calculated electron density of the heterocyclic ring and anti-proliferative activity was observed. Docking of the most active compounds into their putative site of action, the colchicine binding site of tubulin, suggests that they bind through a different mode to the previously described bis-sulfamate derivatives 1 and 2, which possess similar in vitro activity.

Details

Item Type Articles
CreatorsJourdan, F., Bubert, C., Leese, M. P., Smith, A., Ferrandis, E., Regis-Lydi, S., Newman, S. P., Purohit, A., Reed, M. J. and Potter, B. V. L.
DOI10.1039/b810300c
DepartmentsFaculty of Science > Pharmacy & Pharmacology
RefereedYes
StatusPublished
ID Code12436

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